Over the last decade, the prescribing rate of atypical antipsychotics (AAPs) for youth has increased by several folds. This has resulted in a striking contrast between the use of AAPs and the limited scientific evidence regarding their efficacy and safety in the pediatric population. Risperidone is the only AAP to have a pediatric indication by the U.S. Food and Drug Administration based on findings from clinical trials in children with autistic and disruptive behavior disorders. Thus, its proven efficacy in youth, in addition to its potent dopamine D2 receptor blocking activity, makes it unique among AAPs. Concerns, however, have been raised regarding its potential to hinder bone mineral accrual due to hyperprolactinemia, thus increasing the risk of osteopenia and osteoporosis. Furthermore, the propensity of AAPs to increase weight significantly and result in metabolic abnormalities has generated calls to investigate the occurrence of dyslipidemia, glucose intolerance, insulin resistance, and the metabolic syndrome phenotype in youth treated with these potent drugs. By combining a retrospective with a prospective design, this application attempts to address these clinically urgent issues. It builds on an ongoing study investigating the metabolic and hormonal abnormalities associated with the chronic use of risperidone in youth. The retrospective and cross-sectional collection of a variety of clinical and laboratory data, including bone mineral density, has recently been completed. However, the clinical impact of these metabolic and hormonal abnormalities is likely to become significant only after prolonged exposure. Thus, during the two-year period of this study, we propose to increase the current sample size and reevaluate all the patients, 15 months after their baseline enrollment. At follow up, the interim clinical history will be documented and clinical and laboratory measures related to the putative metabolic and hormonal abnormalities will be collected. This application, thus, aims to evaluate the effects of long-term risperidone treatment in youth on bone mineral accrual, weight gain, and lipid and glucose metabolism. It will also test whether variants of the serotonin receptor and leptin genes elevate the risk for risperidone-induced metabolic abnormalities. The result of this work will potentially allow the safer use of this effective medication. Findings from this work will add to the bourgeoning literature addressing the long-term safety of atypical antipsychotics in children and adolescents by evaluating the potential for risperidone to cause osteoporosis and cardiovascular disease by inducing hyperprolactinemia, weight gain, and metabolic abnormalities. Identifying genetic factors that place certain youth at higher risks for such side effects would eventually allow clinicians to tailor treatment to the needs and vulnerabilities of each child by conducting genetic testing before selecting an atypical antipsychotic to prescribe. [unreadable] [unreadable] [unreadable]